JPH02115175A - Piperadine dione having psychotropic action - Google Patents

Abstract

NEW MATERIAL: A compound of formula I [wherein R¹ is H, a (substituted) 1-21C aliphatic group, a (substituted) 3-20C alicyclic group, a 7-32C araliphatic group or the like; R² is R¹ or the like; R³ is H, a (substituted) 1-21C aliphatic group, a (substituted) 3-20C alicyclic group or the like; R⁴ is R¹ or the like; R³ and R⁴ may be combined with each other to form a 3-15C monocyclic, bicyclic or like heterocyclic system] and a salt thereof.

EXAMPLE: (3S,5S,8aS,9aS)-3-methyl-2H-decahydrocyclopenta[4,5]pyrrolo[1,2- a]pyridine-1,4-dione.

USE: Medicines. nootropic agents. Has psychotropic action for the therapy and prophylaxis of disturbances in the central nervous system and is useful for especially the therapy of the dysfunction of recognition.

PREPARATION: A compound of formula II (wherein X¹ is a protective groups such as OCH₃ or OC₂H₅) and a compound of formula III are reacted with each other in the presence of a base and/or a coupling aid in a solvent, and the obtained compound of formula IV is intramolecularly cyclized to obtain a compound of formula I.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel 1,4-piperazine-2,5-dione,
Drugs containing these have psychoactive effects to treat and prevent disorders of the central nervous system, especially cognitive dysfunction! ;nootropic action (nootrop)
ic action).

(3S) -3-(2-methylpropyl) -1,4-
piperazine-2,5-dione (cyclo(Leu -Gl)
y)) have an effect on the central nervous system, in particular decreasing the tolerance to morphine [see Pharmacol, Exp, Thar.
, ) Vol. 218, p. 404 (1981), WP 8
000-216) and acts as an antagonist to the amnesia induced by buromycin [
Pharmacolo Biochem Behavior (Pharmac
o l,.

Biochem, Behav, Volume 1θ, page 787 (1979), Pharmacolo Biochem Behav 7
'(Pharm-acol, Biochem,
Behav, Vol. 8, p. 93 (1978), Japanese Patent No. J54073-133].

Furthermore, piperazine-2,5-dione is used, for example, as an analgesic (J58083-682-A, J59073-5
74-A), as an anti-ulcer agent (European Patent No. 008)
．． No. 186, US Pat. No. 3,976.773) and as a PAF antagonist (European Patent No. 181.152).

The aim of the present invention is to find new compounds with anti-amnestic action.

This purpose is achieved according to the invention by the following two cycloaliphatic radicals substituted by , optionally substituted cycloaliphatic radicals having 4 to 20 carbon atoms, optionally substituted aromatic radicals having 6 to 12 carbon atoms , 7~
optionally substituted araliphatic group having 32 carbon atoms, optionally substituted aromatic heterocycle having 5 to 12 ring atoms or aromatic heterocycle -(C3-C5)-aliphatic R' represents hydrogen, an optionally substituted aliphatic group having 1 to 21 carbon atoms, an optionally substituted alicyclic group having 3 to 20 carbon atoms, 4 Optionally substituted cycloaliphatic groups having ~20 carbon atoms, optionally substituted aromatic groups having 6 to 12 carbon atoms, 7 to
an optionally substituted araliphatic group having 32 carbon atoms, an optionally substituted aromatic heterocycle having 5 to 12 ring atoms or I; )−
represents an aliphatic group or, if not already included in the above definition, an optionally protected side chain of a naturally occurring a-amino acid; R3 is hydrogen, 1 to 21 carbon atoms; an optionally substituted aliphatic group having from 3 to 20 carbon atoms, an optionally substituted cycloaliphatic group having from 3 to 20 carbon atoms, from 6 to 12
an optionally substituted aromatic group having 7 carbon atoms;
represents an optionally substituted araliphatic group having ~32 carbon atoms, R6 is hydrogen, an optionally substituted aliphatic group having 1 to 21 carbon atoms, 3 to 20 carbon atoms; cycloaliphatic radicals, optionally substituted cycloaliphatic radicals having 4 to 20 carbon atoms; optionally substituted cycloaliphatic radicals having 6 to 12 carbon atoms; Substituted aromatic group, 7-
an optionally substituted araliphatic group having 32 carbon atoms, an optionally substituted aromatic heterocycle having 5 to 12 ring atoms or an aromatic heterocycle -(C+ to Ca) only, or R3 and R together with the atoms that have them 3
This is achieved by compounds forming monocyclic, bicyclic or bicyclic heterocyclic ring systems having ~15 ring carbon atoms.

Optionally substituted aliphatic radicals are to be understood as aliphatic acyclic radicals, ie radicals with open straight or branched carbon chains such as alkyl, alkenyl, alkynyl and the corresponding polyunsaturated radicals. It is preferably unsubstituted; for example, hydroxyl, alkoxy, halogen, amine, alkanoylamino, alkoxycarbonylamino, arylalkoxycarbonylamino, arylalkylamino, alkylamino, dialkylamino, alkylthio, arylthio, carboxyl, carbamoyl, Monosubstituted by alkoxycarbonylnoyloxy, alkoxycarbonyloxy, aroyloxy or aryloxycarbonyloxy.

the optionally substituted cycloaliphatic groups and the corresponding optionally substituted cycloaliphatic-aliphatic groups attached to the open carbon chain have single bonds or asymmetrically present double bonds; It may also be branched (i.e. it can have open-chain aliphatic side chains) and preferably monocyclic to pentacyclic rings bonded to ring carbon atoms or to side chain carbon atoms. is a carbocyclic non-aromatic group. Preferably it is unsubstituted. When groups of this type contain more than one ring, they are fused or spiro-bonded. Examples of groups of this type are those derived from cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and mono- or oligocyclic thembene; groups such as menthyl, immenthyl, bornyl, caranyl, ebibornyl, ebiisobornyl. , inbornyl, neomenthyl, neoisomenthyl, vinyl,
It is Tujanil. They are preferably unsubstituted (aliphatic side chains are not substituents according to the definition of the invention)
.

Optionally substituted aromatic groups are preferably aryl such as phenyl, biphenylyl or naphthyl;
It may optionally be mono-, di- or tri-substituted as indicated in the explanation for (CS-C1□)aryl below. Groups derived from aryl, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, may be substituted in the same way as aryl.

The optionally substituted aromatic heterocyclic groups preferably have up to 5 to 7 or 8 to 12, preferably up to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen. aromatic monocyclic or bicyclic heterocyclic groups in which the atoms and/or 1 to 4 ring atoms represent nitrogen atoms, such as thienyl, benzoCb) thienyl, furyl, pyranyl, benzofuryl, pyronyl; , imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, isoindolyl, indolyl, purinyl, quinolidinyl, inquinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxasilyl, isoxasilyl, thiazolyl, or inthiazolyl. These groups may also be partially or fully hydrogenated. Aromatic heterocyclic group and corresponding aromatic heterocyclic ring -
Aliphatic groups may be substituted as defined below.

Optionally substituted araliphatic groups are especially arylalkyl groups such as arylalkyl, diarylalkyl,
It is understood to be indanyl or fluorenyl (aryl being a radical as defined below and optionally substituted as described therein).

R3 and R' together with the atoms that carry them have from 3 to 15 ring carbon atoms and preferably up to 2 sulfur atoms and up to 2 nitrogen atoms in the ring, especially up to 1 Monocyclic, bicyclic or bicyclic heterocyclic ring systems can be formed having sulfur atoms.

Particularly suitable ring systems of this type are those selected from the following group:

Pyrrolidine (0), thiazolidine (R), tetrahydroisoquinoline (A), decahydroisoquinoline (B),
Octahydroindole (C), Indoline (Q)
, octahydrocyclopenta[b)pyrrole (D), 2
-Azaspiro(4,53 decane (E), 2-Azaspiro(4,4) nonane (F), spiro[(bicyclo(2,2)
, 1) Hebutane]-2,3'-pyrrolidine) (G), Spiro[(bicyclo(2,2,2)octane) -2,3
'-pyrrolidine] (H), 2-azatricyclo(4,3
,0,1'-)decane (I), decahydrocyclohebuta (bl pyrrole (J), octahydroisoindole (
K), octahydrocyclopentaCC) pyrrole (L
), 2.3.3a, 4,5,7a -hexahydroindole (M), 2-azabicyclo(3,1,O)hexane (N), 1.2.3,3a, 4.6a -hexahydro '7 Clopenta (b) Pyrrole (P) (all of which may be optionally substituted). Pyrrolidine CO> and thiazolidine (R) are, for example, (C, ~
C1□)-aryl (phenyl, 2-hydroquinphenyl, etc.), (C, ~C+ 2)-arylmercapto (
e.g. phenylmercapto) or (03-C7)-
It may also be monosubstituted by cycloalkyl (eg cyclohexyl). The same applies to other ring systems. However, unsubstituted systems are preferred.

In the case of compounds of the formula I with more than one chiral atom, mixtures of the various diastereomers are suitable as racemates or enantiomers.

A suitable heterocyclic ring system has the following structural formula.

Preferred specific examples include formula I [wherein, R1 is hydrogen, (C+ -Cra)-alkyl, formula C
aH(2a-b+ + 1 (However, if the number of double bonds is greater than 1, they are not integrated, and a is an integer from 2 to
18 and b represents an even number from 2 to a), an aliphatic acyclic group of the formula C3HI2°-d-1+ (?:
In the dashi formula, C represents an integer from 3 to 20, and d represents an even number from O to (c-2)). Hydrogen group, (CI-CS)-alkyl, (01-C,)-alcoquine, hydroxyl, halogen, nitro, amino,
Aminomethyl, (C+~C4)-alkylamino, di(C1-C4)-alkylamino, (01~C4)-alkanoylamino, methylenedioxy, carboxyl,
monosubstituted by cyanide and/or sulfamoyl,
May be di- or tri-substituted (CS~
C+ z)-aryl, amino-(C+~CS)alkyl, (01~C4)-alkanoylamino-(C+~c
m)-Alkyl, (C7-C1,)-aroylamino-
(C+~C5)-alkyl, (C+~C4)alkoxycarbonylamino=(C1~C3)-alkyl, (CO
~C1,)-aryl-(C+~C4)alkoxycarbonylamino-(C8~C3)-alkyl, (CS~C
+ i)-Aryl-(C, ~C4)alkylamino-
(C+ -Ca)-alkyl, (C+~C,)-alkylamino-(C,~C5)-alkyl, di(C+~
C4)-alkylamino-(C,~Ca)-alkyl,
Guanidino-(C+~Ca)-alkyl, (CI-C4
)-alkylthio-(01~c,)alkyl, (C,~
C,□)-arylthio-(C.

~C,)-alkyl or (Ca~C+ 2)-aryloxy-(CI-Ca)-alkyl (both latter two optionally substituted as above in the aryl moiety), carboxy-(C+ ~c17) alkyl, (
01-C4)-alkoxycarbonyl-(C3-C+
7) -Alkyl, carbamoyl-(CI-CI7)-alkyl, (CI-C4) %/ *or -di-alkylcarbamoyl-(01~cl□)-alkyl (however, alkyl may be (Ca-C1□) )-aryl), R2 is hydrogen, (C+ -01m )-alkyl, formula Ca
H+za-b+ + 1 (wherein, double bonds are not cumulative if their number is greater than l, a represents an integer from 2 to 18, and b represents an even number from 2 to a) ) aliphatic acyclic group, 2〇〇〇(IC-d
-11 (wherein, C represents an integer from 3 to 20, and d represents an even number from 0 to (c -2)), depending on the case, branched monocyclic, bicyclic, pentacyclic ,
Tetracyclic or pentacyclic non-aromatic hydrocarbon group, (CS to C
+ t)-aryl, (C6~C1□)-aryl-(
C+~Ca)-alkyl or (Cy~C1s)-
aroyl-(Ct-CS)-alkyl, each of which may be substituted as above in the aryl moiety, having 5 to 7 or 8 to IO ring atoms, of which 9 up to ring atoms represent carbon, 1 to 2
ring atoms represent sulfur or oxygen, and/or;
is a monocyclic or bicyclic optionally partially hydrogenated heteroaryl or heteroaryl-(C+~cm)-alkyl in which 1 to 4 ring atoms represent nitrogen, each of which represents aryl may be substituted as described above), and if not already present, the formula R'-CH (NH-
23 and R4 together with the atoms that carry them represent a monocyclic, bicyclic ring having from 3 to 15 ring carbon atoms; [forms a polycyclic or pentacyclic heterocyclic ring system]
The following compounds can be mentioned.

Particularly preferred compounds (2) are those in which R1 is hydrogen, (C+~cm)-alkyl, (C2~C0
)-alkenyl, (03-C9)-cycloalkyl, (
C+~C4)-alkyl, (C+~C,)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1~Ct)-alkylamino, di(C+~
C4)-alkylamino, (C+~C,)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl having 5 to 7 or 8 to 10 ring atoms, respectively 1 to a monocyclic or bicyclic heteroaryloxy in which two ring atoms represent sulfur or oxygen atoms and/or one to four ring atoms represent nitrogen (as defined above for aryl); may be mono-, di- or tri-substituted (C6
~C1□)-aryl, amino-(C, ~C,)-alkyl, (C+~C4)-alkanoylamino-(C+~
C,)-alkyl, (cy~C1,)-aroylamino-(CI-C< )-alkyl, (01~C1)-alkoxycarbonylamino-(C,~C1)-alkyl,
(CS~C□,)-aryl-(C,~C4)-alkoxycarbonylamino-(C,~C6)-alkyl, (
G s ” C+ z )-aryl-(cr ~ C
4)-alkylamino-(at~C4)-alkyl, (
C+~C4)-alkylamino-(c+-C4)-alkyl, di(C+~Ct)-alkylamino-(C,~
Ct)-alkyl, guanidino-(C+~C4)-alkyl, (C+~C4)-alkylthio-(C+~C4)
-alkyl, (ci~C02)-arylthio-(C+
-C4)-alkyl, which may be substituted in the aryl moiety as described above for aryl, R2 is hydrogen, (C, -C6)-alkyl, (02-c,
) alkenyl, (CZ-C5)-alkynyl, (C, ~
Ct)-cycloalkyl, (C6-C3)-cycloalkenyl, Ccs-C5)-cycloalkyl-(C+-C
4) -Alkyl, (CS-C9)-cycloalkenyl-
(C1-Ct)-alkyl, optionally partially hydrogenated (cg-C1□)-aryl, which may be substituted as described above for R1,
(Ct-Ctz)-aryl-(01~Ca)-7
Roxy or (C6-C1□)-alloy/L-(Ctmatahac2)-alkyl (both of which may be substituted in the same way as the aryls above), 5 to 7 or 8
~IO ring atoms, each one of them ~
The two ring atoms represent sulfur or oxygen atoms, and /
or a monocyclic or bicyclic optionally partially hydrogenated heteroaryl in which 1 to 4 ring atoms represent nitrogen atoms, which may be substituted in the same way as the aryls above, or a naturally occurring σ-amino acid R'-CH
represents an optionally protected side chain of (NO3)-COOH and is a compound when R3 and R4 have the meanings given above.

Particular mention may be made of compounds of the formula (■) in which R1 is hydrogen;
(C+~cm)-alkyl, (02-C3)-alkenyl, (CS-C1)-cycloalkyl, amino-(CI
-C,)-alkyl, Ccx~C5)-acylamino-
(fl,, -C,)-alkyl, (Ca~C1,)-arooylamino-(CI-C4)-alkyl, (C+~
C4)-Alkoxycarbonylamino-(C1-C4)
-Alkyl, (C, ~C4)-alkoxycarbonyl-
(C1~C1゜)-alkyl, carbamoyl-(C,~
Cl0)-alkyl, (C+-C4)-mono- or di-alkylcarbamoyl-(C3-C1°)-alkyl (alkyl optionally substituted with phenyl),
(cs~C1□)-aryl-(CI-Ca)-alkyl, (Ca-C1□)-aryl-(C+~C4)-
Alkoxycarbonylamino-(C1-C1)-alkyl, (C+-Ct)-alkyl, (C,-C4)-alkoxy, hydroxyl, halogen, nitro, amino, (
C+~C,)-alkylamino, di(C+~C4)-
(C8-Cl0)-Aryl, which may be mono-, di- or tri-substituted by alkylamino and/or methylenedioxy, in particular hydrogen, methyl, ethyl, tertiary-butoxycarbonylamino=(C1-C4
)-alkyl, benzoyloxycarbonylamino-C
C+~Ca)-alkyl, Ca/lzpoxy (C8~C
l0)-A/l, kyl, (ct~C4)-alkoxycarbonyl-(01~C1°)-alkyl, R2 is hydrogen, optionally substituted by amine, (C1~C5)-acylamino or benzoylamino; (C,~C5)-alkyl, (CZ~Ca
)-alkenyl, (C3-C5)-cycloalkyl, (
cs-ct) -cycloalkenyl, (Ci~Ct)cycloalkyl-(C+~C,)-alkyl, (cm~C
1,)-aryl or partially hydrogenated aryl, which are (ct-C4)-alkyl, (C1
or CZ)-alkoxy or halogen), (Ca-C1□)aryl-(C
1 to Ca)-alkyl or Cct to C1,)-aroyl-(CI-C2)-alkyl, both of which may be ril substituted as defined above in the aryl group, 5 to 7 or monocyclic having 8 to 10 ring atoms, each of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms or bicyclic heterocyclic groups, or side chains of naturally occurring optionally protected α-amino acids, in particular hydrogen, (C+ to CZ)-alkyl,
(C3mat: represents C3)-alkenyl, an optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, and R3 and R4 together with the atom holding them form octahydroindole, octahydrocyclopenta(
b) Virol, spiro [(bicyclo(2,2,2)octane)-2,3'-pyrrolidine], i, 2,3,3a,
4.6a-hexahydrocyclopentaCb) A compound selected from the group consisting of virol or indoline when forming a bicyclic or bicyclic heterocyclic ring system.

Side chains of naturally occurring α-amino acids with R2 protected, e.g. protected Ser, Tbr, Asp, Asn
.

Glu, Gin, Args Lys, Hyl,
CYSXOrr+, Cit.

When representing Tyr, Trp or His, preferred protecting groups are the groups commonly used in peptide chemistry [see Houben-Wey, Volumes XV/1 and XV/2]. When representing the side chain of lysine, known amino protecting groups are preferred, especially ZtBoc or (C+-C5)-alkanoyl. Suitable and preferred 0-protecting groups for tyrosine are (C+-C6) -alkyl, especially methyl or ethyl.

The present invention also relates to a process for preparing a compound of formula (1) in a suitable solvent and, if appropriate, a base and/or
or by reacting the fragments described above in the presence of a coupling auxiliary agent, if appropriate to reduce the unsaturated compounds formed as intermediates, such as thick bases, and to temporarily introduce them in order to protect the reactive groups. removing the protective groups thus obtained, subjecting the compound thus obtained to intramolecular cyclization, esterifying the compound of formula 1 with free carboxyl groups, if appropriate, and The process consists of converting the compound to a point where it is physiologically acceptable.

For example, compounds of formulas ■ and ■ are reacted by the method of formula ■ (where ■ ~
■In the formula, R1-R4 are defined as shown above,
xl is (C1-CM)-alkoxy, (cy~C7,) as a protecting group that is temporarily introduced for a carboxyl group that does not participate in the reaction and can be removed by a known method after the reaction is completed. -arylalkoxy, (C
+~C1)-alkylamino, (C7~C+3)-arylalkylamino, preferably methoxy, ethoxy, benzyloxy, tertiary butoxy, and X2 is an amino group known in peptide synthesis. Protective groups for
Author: Wey1 Meth, d, organ.

ChemieJ) Volumes
Protective Groups in Orga
nicSynthesisJ), New York (1
981), for example tertiary-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, which can also be removed again in a manner known per se after the reaction has taken place. can be generated.

The compound of formula 1 according to the present invention can be obtained by intramolecularly cyclizing the compound of formula (1) by the above method, either with the group X1 still present, or after separately removing X1 to form a carboxyl group. can be done.

The reaction of these compounds can be carried out analogously to known peptide coupling methods in organic solvents such as dimethylformamide (DMF), methylene chloride (CH2Cα2), dimethylacetamide (DMA) and with coupling aids such as carbodiimides in solvents such as acetonitrile. (eg dicyclohexylcarbodiimide), difuunylphosphoryl azide, alkanephosphonic anhydride, dialkylphosphinic anhydride or N,N'-disuccinimidylic acid anhydride. The amino group in the compound of formula (1) can be activated with tetraethyl diphosphite. Compounds of formula II can be converted into active esters (e.g. using 1-hydroxybenzotriazole), mixed acid anhydrides (e.g. using chloroformic esters), azide or carbodiimide derivatives and thus activated. [Zapebutide J (Sc
The Pept by Messrs. Hroder and Lubke
ides J), Vol. 1, pp. 76-136, 1965, New York]. The reaction is preferably carried out at a temperature from -20°C to the boiling point of the reaction mixture.

However, the reaction to give compounds of formula (1) can also be carried out thermally in a suitable organic solvent at temperatures from O'C to the boiling point of that solvent.

Similarly, formulas ■ and ■ Xl0C-CH-NH-R' HOOC-CH
-N-X2R2RI R4 (V) (Vl
) can be linked in the manner described above to give a compound of formula (1) and then cyclized to give a compound of formula I.

Similarly, the compound of formula (■) C-CM-N-C-CH-NH' RJ R3R2 (■) is reacted with the compound of formula (■) 1, where R1, R2, R3, R' and xl are as defined above and Yl represents a leaving group)
can also be generated. Examples of suitable leaving groups are chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy.

This type of alkylation can be carried out in water or in organic solvents such as dichloromethane or other aliphatic alcohols (f:,!:
, ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ether.
C. to the boiling point of the reaction mixture and in the presence of a base such as an alkali metal hydroxide or an organic amine.

Also, for example, by using alkylation methods well known to those skilled in the art [e.g.
Method of Organic Chemistry (by Mr. Howben-Weyi)
n der organischan ChemieJ
), Vol. It is also possible to prepare novel compounds of the general formula (1) by reaction with alkylating agents of the general formula (1), such as alkyl halides.

The two-tropic effect of the compounds according to the invention is
tested in the inhibitory (passive) avoidance test (step-through model) using 25g mice; Zeikopp, Z. Bodanecky and M.J. Kopp, L. Bodanecky and M.
A modification of the test method described by Zeibles, Øblesová and Zeyhaston (J.
, Bures, O. Buresova and J. Hu.
``Techniques and basic experiments for research on the brain and behavior'' by
d Ba5ic Experiments for t
he 5 studies of Brain and Beha
vior), (Elsepia Scientific Publishing, Amsterdam, 1983).

This document states that a substance may be nooLropic if it is able to counteract the amnesia induced in experimental animals by electroconvulsive shock or amnesia induced by scopolamine.
It is said to be active.

The experiment was conducted using a modified test method. The comparison compound used was 2-oxo-, a known two-tropic agent.
1-Pyrrolidinyl acetamide (Viracetam).

The significant superiority of the compounds according to the invention over the above-mentioned comparative substances is demonstrated by their ability to suppress amnesia induced by scopolamine in the inhibitory avoidance test at an oral MED (Jt low effective dose i) of 1.0-30 mg/Jzg. This is clear from the fact that it can be erased. The above comparative substances have an oral MED of approximately 500-1.000 mg/kg.

In general, the compounds according to the invention have very low toxicity and, because of their pharmacological properties, are suitable for treating cognitive dysfunctions of various etiologies, which occur, for example, in Alzheimer's disease or senile dementia.

Furthermore, the present invention includes medicaments containing the above-mentioned compounds, processes for their manufacture, and the use of the compounds according to the invention in the manufacture of medicaments used to treat and prevent the above-mentioned diseases.

The medicaments are known per se and manufactured by methods familiar to those skilled in the art. Pharmacologically active compounds according to the invention (-
active substance) as such or preferably in combination with suitable pharmaceutical auxiliaries as tablets, coated tablets, capsules, detents, emulsions, suspensions or solutions, in which case the active substance content is approx. 95%, preferably 10-75%).

The specific adjuvants suitable for the desired pharmaceutical formulation are well known to those skilled in the art on the basis of their expertise. In addition to solvents, gel formers, stopper bases, tablet adjuvants and other excipients for the active substance, e.g. antioxidants, dispersants, emulsifiers, antifoaming agents, flavoring agents, preservatives, Solubilizers or colorants can be used.

The active substance can be administered, for example, orally, rectally or parenterally (eg intravenously or subcutaneously), although oral administration is preferred.

For forms for oral use, the active compound is mixed with suitable excipients for this purpose; e.g. excipients, stabilizers or inert diluents and prepared in the usual manner into suitable dosage forms, e.g. tablets. , coated tablets, hard gelatin capsules,
into aqueous, alcoholic or oily suspensions or solutions. Examples of inert excipients that can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, especially corn starch.

The production can be carried out both as dry granules and as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compound or its physiologically tolerable salt may be prepared in solution, optionally together with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Make into a suspension or emulsion. Examples of suitable solvents are water, saline or alcohols such as ethanol, propatool and glycerol, and sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned above.

Example 1 (3S, 5S, 8aS, 9aS) -3-methyl-2H
-Decahydrone clopenta(4,5)pyrrolo CI, 2-
a) Pyrazine-1,4-dione a) Dimethylformamide 680m (benzyl (Is, 3s, 5S) in +) -2-azabicycloC3,3,
0) 41.29 g of octane carboxylate and 34.8 g of N-tert-butoxycarbonyl-di-alanine
116 ml of triethylamine and n-propylphosphonic anhydride (n-Prop
170rn+2 of a 50% solution of PA) are added and the mixture is stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate IQ and twice with saturated sodium bicarbonate solution.
Washed twice with 10% citric acid solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum to give an oily consistency. Yield: 65.9 g of colorless oil.

[α3g--52,2° (c-1, in methanol).

b) Benzyl 2-(N-37th) as described in a)
'Toxycarponyl-S~alanyl) -(Is.

3S, 5S) -14.6g of -2-azabicyclo(3,3,0)octanecarboxylate was dissolved in trifluoroacetic acid 2
Stir with 5++112 at 0° C. for 30 minutes and then at room temperature for 2 hours. The solution is concentrated under vacuum and the operation is repeated three times, each time adding 10 mQ of toluene and concentrating again. The residue obtained in step 2 is refluxed in 100 mQ of ethyl acetate for 9 hours. After cooling the reaction solution, 4.06 g of colorless crystals having m, p, 222°C were obtained. [ff)==+3.12°(
c=1 in methanol).

Example 2 (3S, 5R, 8aR, 9aR) -3-methyl-2H
-decahydrocyclopenta(4,5) pyrroloC1,,
2-a) Pyrazine-1,4-dione a) Benzyl 2-(N-tert-butoxycarbonyl-5-
alanyl') -(lR,3R,SR) -2-azabicyclo(3,3,0:]octanecarboxylatebenzyl(IR,3R,5R) -2-azabicycloC
3,3,0) octane carboxylate 4.919 and N-tert-butoxycarbonyl-shi-alanine 4.12
Dissolve g in 80 mQ of anhydrous dimethylformamide and add at 0'C 12.7 rnQ of N-ethylmorpholine and 20.2 rfIQ of n-propylphosphonic anhydride (50% in methylene chloride). The reaction mixture is stirred at room temperature for 5 hours.

After adding 120 mff of ethyl acetate, the mixture is washed twice with saturated sodium bicarbonate solution, twice with 10% citric acid solution and once with saturated saline. After drying and concentrating the organic phase, 8.04 g of a viscous oil remains. [α) 16-97.2° (c=1. in methanol).

b) 7 g of the oil obtained in a) was mixed with 290 g of ethanol.
Hydrogenate using palladium-charcoal powder in a mff at room temperature. The catalyst was separated in the furnace and the solution was concentrated.
p, 5.5 g of colorless solid at 140° C. remain.

c) 1 g of the carboxylic acid obtained in b) is treated with 5 mΩ of trifluoroacetic acid at o'c for 45 minutes.

The solid residue obtained after concentration is refluxed in an Improper Tool for 9 hours. The solvent is removed under vacuum and the residue is recrystallized from ethyl acetate. colorless crystal 435
m9 is obtained.

m, p, 214°C0 Example 3 (3S, 5S, 8aS, 9aS) -3-Schif0hexylmethyl-2H-decahydrocyclopenta(4,5)pyrrolo(1,2-a)pyrazine-1, 4-dione a) N-
3rd;' Toxicarponyl-L-cycvhexylalanine 5.7g and benzyl (Is, 3S.

5S)-2-79bicycloC3-3,0) 5.5 g of 9-h rupoxylate were dissolved in 55 m of methylene chloride/dimethylformamide 10:1 (2) and mixed with Q'O to 15 m of N-ethylmorpholine and n-Propylphosphonic anhydride (5 in methylene chloride)
0%) Add 24m12. The reaction solution is stirred at room temperature overnight, diluted with 150 i (2) methylene chloride, and extracted with saturated sodium bicarbonate, 10% citric acid, and saturated brine. The organic phase is dried and concentrated to a brown oil. is obtained and purified by column chromatography (silica gel, cyclohexane/ethyl acetate). Yield: 7.9 g of colorless oil. [σ]
H=-29,9° (c=1 in methanol).

b) Dissolve 1.5 g of the oil obtained in a) in 7 mQ of dimethoxyethane saturated with hydrogen chloride and stir the solution for 0.5 h at room temperature. This solution is evaporated to dryness. The residue is dissolved in 20 mO of Improper Tools and refluxed for 6 hours. Colorless crystals 45h+9 are obtained by cooling this solution and filtering it with suction. m, p,
239°C0 Example 4 (3S, 5S, 8aS, 9aR) -3-methyl-2N
-(3-phenylpropyl)-2H-decahydrocyclopenta(4,5)pyrrolo(1,2-a)pyrazine-1,
4-Dione 1 g of piperazine-2,5-dione as described in Example ■
was dissolved in 20 m (l) of dimethylformamide with OoC,
Then add 0.567 of potassium tertiary butyrate.

After 45 minutes of reaction, a clear yellow solution is formed, to which 0.73 mQ of 3-phenylpropyl furomide is added dropwise. After being held at 0°C for 2 hours, the solution was allowed to warm to room temperature, then poured into water, and the mixture was diluted with ethyl acetate for 3 hours.
Extract twice, dry the organic phase and concentrate. Purification by chromatography (silica gel, cyclohexane/ethyl acetate) gives 1.04 g of colorless crystals. m
, p, 92°O, [a): −+ 127.5°(c
−1° in methanol).

Example 5 (3S, 5S, 8aS, 9aR) -3-
Methyl-2N-octyl-2H-decahydrocyclopenta(4,5)pyrrolo(1,2-a)pyrazine-1,4
-Diones 2 g of piperazine-2,5-dione as described in Example 1 are dissolved in 50 rms of dimethylformamide and 1.1 ml of potassium tert-butyrate is dissolved under ice cooling.
Add 2g. n-octyl bromide 1.6 after 40 minutes
6+nQ is added dropwise and the reaction mixture is stirred overnight. The solution is diluted with water and extracted several times with ethyl acetate. The organic phase is dried and concentrated to give an oily crude product 3
．． 39 remain. Silica gel chromatography (
When purified by cyclohexane/ethyl acetate), m, p
, 1.1 g of the desired product are obtained at 44-47°C.

[σ)zo=1156.1° (C-1, in methanol)
.

Example 6 (3S, 5S, 8aS, 9aS) -3-methyl-2N
-(1S-ethoxycarbonylbutyl)-2H-decahydrocyclopenta[4,5:]pyrrolo(1,2-a
) pyrazine-1,4-dione a) N-(1-R,S-ethoxylponylheptyl)
-L-Alanine benzyl ester L-Alanine benzyl ester 6.2 g of ate are added and the mixture is stirred for 24 hours. The reaction solution is concentrated, the residue is dissolved in ethyl acetate, the solution is washed with ammonium chloride solution and sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting 6.2 g of crude product is separated into two diastereomeric products by column chromatography (silica gel, cyclohexane/ethyl acetate). The less polar diastereomer is obtained in a yield of 2.2 g. The more polar diastereomer is obtained in a yield of 1.6 g.

[σ>r−−31,2°(c−1,)9)−r).

b) N-(1-5-ethoxycarbonylheptyl)-L
-Alanine benzyl ester (polar diastereomer) 3.2
g of palladium/charcoal powder in 130 mQ of ethanol.
Hydrogenate using mg. After the reaction is complete, the catalyst is removed and the solvent is distilled off under vacuum. The yield is 2.
It is 2g.

(ff) r-+9.2° (c-1, meta/-71, medium)
.

C) Benzyl 2-(N-(1-3-ethoxycarbonylbutyl)-S-alanyl)-(Is.

3S, 5S) -2-3 g of carvone m obtained with -2-azabicyclo(3,3,0)octane-3-carboxylate b) and benzyl (
1, S, 3S, 5S) -2-7 Zabinkuro (3, 3,
0) Dissolve 2.3 g of octane-3-carboxylate in anhydrous dimethylformamide 110+cQ and -8
6.0 mQ of triethylamine and 8.2 m (l) of n-propylphosphonic anhydride are added at <0>C.

After stirring for 48 hours at room temperature, the solution is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, 10% citric acid and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 3.9 g of the crude product was subjected to silica gel column chromatography (cyclohexane/
Purification by ethyl acetate gives 1.2 g of pure material. [α] pi = -46,6° (c = 1, in methanol).

d) 2-CN-(1-3-ethquincarbonylhebutyl)-S-alanyl) -(Is, 3S, 5S)2
- azabicyclo(3,3,0)octane-3-carboxylic acid 1.2 g of ester (see above (c)) in ethanol 5
Hydrogenation using 250 mg of palladium/charcoal powder in 0 m+2. After the reaction is complete, the catalyst is removed and the solution is concentrated. Yield is 910 mg. (α:]
r-+5.3° (c-1 in methanol).

e) 400 mg of the carboxylic acid obtained in d)
h) Dissolve in 10 mff of dimethylformamide with 156+ ng of loxybenzotriazole and 208 mg of dicyclohexylcarbodiimide and stir overnight. The solution is filtered to remove precipitated dicyclohexyl sulfate, mixed with ethyl acetate, washed with saturated sodium bicarbonate solution, 10% citric acid and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is stirred with petroleum ether and the crystals that form are exposed to suction.

Yield is 170 mg. (g)%'-41-1°(c
−1° in methanol).

Example 7 (3S, 5S, 8aS, 9aS) -3-methyl-2N
-(1-R-ethoxycarbonylbutyl)2H-decahydrocyclopenta C4,5)pyrroloC1,2-a)
Pyrazine-1,4-dione The less polar diastereomer obtained in Example 6a) is reacted as described in 6b) to d). 2-CN-(1-R-ethoxycarbonylheptyl)-3-alanyl)-(Is.

3S, 5S) -2-7 Zabishi'7 mouth [3,3,0)
O'797-3-carboxylic acid 55 (JmgC(α)%
= + 4.4° (c -1 in methanol)] is reacted with 215 mg of 1-hydroxybenzotriazole and 290+++ g of dicyclohexylcarbodiimide in 14 ml of anhydrous dimethylformamide. 4 at room temperature
The reaction is complete after stirring for 8 hours. Work-up is carried out as described in Example 6e). Yield: colorless oil 33
It is 0 mg. [σ]%'--3,7'(c -1,
in methanol).

Example 8 (3S, 6S, 7aS) -3-methyl-6-nixose spiro(bicyclo[2,2,2)octan-2-yl)
-2N-(1-S-Ethoxycarbonyl-3-phenylpropyl)octahydropyrrolo[l,2-a) Pyrazine-1,4-dione N-(1-5-ethoxycarbonyl-3 in 5 mQ of anhydrous dimethylformamide -phenylpropyl)-8-alanyl-exo-spiro(bicycloC2,2,2)octane-2,3-pyrrolidin)-5-yl-carboxylic acid 0.
4 g are stirred with 130 mg of 1-hydroxybenzotriazole and 75 mg of dicyclohexylcarbodiimide L overnight at room temperature. The precipitated dicyclohexyl 7 group is removed, the filtrate is diluted with ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid and saturated sodium chloride solution, and then dried over magnesium sulfate.

The crude product remaining after distillation is chromatographed on silica gel (cyclohexane/ethyl acetate).

Yield is 0.2 g of desired product. Mass spectrum:
m/e=452M+.

Patent applicant: Hoechst Akchengesellschaft and 2 others

Claims (1)

[Claims] 1) The following formula I ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 is hydrogen, has 1 to 21 carbon atoms, and is optionally substituted. optionally substituted aliphatic groups having 3 to 20 carbon atoms, optionally substituted cycloaliphatic groups having 4 to 20 carbon atoms, 6 ~12
an optionally substituted aromatic group having 7 carbon atoms;
an optionally substituted araliphatic group having ~32 carbon atoms, an optionally substituted aromatic heterocycle or aromatic heterocycle --(C_1 to C_8
)-represents an aliphatic group, R^2 is hydrogen, an optionally substituted aliphatic group having 1 to 21 carbon atoms, 3 to 20
an optionally substituted cycloaliphatic group having 4 carbon atoms;
optionally substituted cycloaliphatic groups having ~20 carbon atoms; optionally substituted aromatic groups having 6 to 12 carbon atoms; 7 to 32 carbon atoms; an optionally substituted aromatic aliphatic group having 5 to 12 ring atoms, an optionally substituted aromatic heterocycle or an aromatic heterocycle-(C_1-C_8)-aliphatic group having 5 to 12 ring atoms, or Naturally occurring α if not already included in the definition
- represents an optionally protected side chain of an amino acid, R^3 being hydrogen, an optionally substituted aliphatic group having 1 to 21 carbon atoms, having 3 to 20 carbon atoms; optionally substituted cycloaliphatic groups having 6 to 12 carbon atoms, optionally substituted aromatic groups having 7 to 32 carbon atoms; R^4 is hydrogen, an optionally substituted aliphatic group having 1 to 21 carbon atoms, an optionally substituted alicyclic group having 3 to 20 carbon atoms, 4 to 20 optionally substituted cycloaliphatic groups having from 6 to 12 carbon atoms; optionally substituted aromatic groups having from 6 to 12 carbon atoms;
optionally substituted araliphatic group having 32 carbon atoms, optionally substituted aromatic heterocycle or aromatic heterocycle having 5 to 12 ring atoms -(C_1 to C_8)
-represents an aliphatic group, or ▲represents a mathematical formula, chemical formula, table, etc.▼, or R^3 and R^4 together with the atoms that carry them represent from 3 to 15 ring carbon atoms; (forming a monocyclic, bicyclic or tricyclic heterocyclic ring system) and physiologically acceptable salts thereof. 2) Formula I according to claim 1 [wherein R^1 is hydrogen, (C_1-C_1_8)-alkyl, formula CaH_(_2_a_-_b_+_1_) (however, if the number of double bonds is greater than 1) Not accumulated,
a represents an integer from 2 to 18, and b represents an even number from 2 to a), an aliphatic acyclic group of formula C_cH_(_2_c_-_d_-_1_) (wherein c represents an integer from 3 to 20 and d is from 0 to (c
-2) optionally branched monocyclic, bicyclic or tricyclic non-aromatic hydrocarbon groups (representing an even number up to 2);
C_1-C_8)-alkyl, (C_1-C_4)-alkoxy, hydroxyl, halogen, nitro, amino,
Aminomethyl, (C_1-C_4)-alkylamino,
Di-(C_1~C_4)-alkylamino, (C_1~
C_4) - Can be mono-, di- or tri-substituted by alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl (C_6-
C_1_2)-aryl, amino-(C_1 to C_8)
-Alkyl, (C_1-C_4)-alkanoylamino-(C_1-C_8)-alkyl, (C_7-C_1_
3)-Aroylamino-(C_1-C_8)-alkyl, (C_1-C_4)-alkoxycarbonylamino-
(C_1-C_8)-alkyl, (C_6-C_1_2
)-aryl-(C_1-C_4)-alkoxycarbonylamino-(C_1-C_8)-alkyl, (C_6
~C_1_2)-aryl-(C_1-C_4)-alkylamino-(C_1-C_8)-alkyl, (C_1
~C_4)-alkylamino-(C_1-C_8)-alkyl, di-(C_1-C_4)-alkylamino-(
C_1~C_8)-alkyl, guanidino-(C_1~
C_8)-alkyl, (C_1-C_4)-alkylthio-(C_1-C_8)-alkyl, (C_6-C_1
_2)-arylthio-(C_1-C_8)-alkyl or (C_6-C_1_2)-aryloxy-(C
_1-C_8)-alkyl (the latter two may both be substituted as above in the aryl moiety), carboxy-(C_1-C_1_7)-alkyl, (C_1-C
_4)-Alkoxycarbonyl-(C_1 to C_1_7
)-Alkyl, carbamoyl- (C_1 to C_1_7)
-alkyl, (C_1-C_,)-mono- or -di-
Alkylcarbamoyl-(C_1-C_1_7)-alkyl (however, alkyl may be (C_6-C_1_
2)-aryl), R^2 is hydrogen, (C_1-C_1_8)-alkyl, formula CaH_(_2_a_-_b_+_1_) (provided that in the formula, if the number of double bonds is greater than 1) a is an integer from 2 to 18 and b is an even number from 2 to a), an aliphatic acyclic group of formula C
_cH_(_2_c_-_d_-_1_) (wherein c represents an integer from 3 to 20, and d represents an even number from 0 to (c-2)), optionally branched monocyclic, bicyclic; Cyclic, tricyclic, tetracyclic or pentacyclic non-aromatic hydrocarbon group, (C_6-C_1_2)-aryl, (C_6-C_1
_2)-aryl-(C_1-C_8)-alkyl or (C_7-C_1_3)-aroyl-(C_1-C_
8) -alkyl, each of which may be substituted as above in the aryl part, 5 to 7 or 8 to 1
0 ring atoms, of which up to 9 ring atoms represent carbon, 1 to 2 ring atoms represent sulfur or oxygen, and/or 1 to 4 ring atoms represent nitrogen a monocyclic or bicyclic optionally partially hydrogenated heteroaryl or heteroaryl-(C_1-C
_8)-alkyl, each of which may be substituted as described above for aryl in the heteroaryl moiety, or if not included in the above definition, of the formula R^1-CH(NH_2)- represents the optionally protected side chain of the naturally occurring α-amino acid of COOH;
^3 and R^4 together with the atoms holding them form a monocyclic, bicyclic or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms] and their Physiologically acceptable salts. 3) Particularly preferred compounds of formula I are those in which R^1 is hydrogen, (C
_1-C_8)-alkyl, (C_2-C_8)-alkenyl, (C_3-C_9)-cycloalkyl, (C_
1-C_4)-alkyl, (C_1-C_4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C_1-C_4)-alkylamino, di-
(C_1-C_4)-alkylamino, (C_1-C_
4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, 5-7
or 8 to 10 ring atoms, each of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen or may be mono-, di- or tri-substituted by bicyclic heteroaryloxy (which may be substituted as described for aryl in claim 2 above) (C_6-
C_1_2) Aryl, amino-(C_1-C_4)-
Alkyl, (C_1-C_4)-alkanoylamino-
(C_1-C_4)-alkyl, (C_7-C_1_3
)-aroylamino-(C_1-C_4)-alkyl,
(C_1-C_4)-Alkoxycarbonylamino-(
C_1-C_4)-alkyl, (C_6-C_1_2)
-Aryl-(C_1-C_4)-alkoxycarbonylamino-(C_1-C_4)-alkyl, (C_6-
C_1_2)-aryl-(C_1-C_4)-alkylamino-(C_1-C_4)-alkyl, (C_1-
C_4)-alkylamino-(C_1-C_4)-alkyl, di-(C_1-C_4)-alkylamino-(C
_1~C_4)-alkyl, guanidino-(C_1~C
_4)-Alkyl, (C_1-C_4)-alkylthio-(C_1-C_4)-alkyl, (C_6-C_1_
2)-Arylthio-(C_1-C_4)-alkyl(
(optionally substituted as described in claim 2 above for aryl in the aryl moiety), R^2 is hydrogen, (C_1-C_6)-alkyl, (C_
2-C_6)-alkenyl, (C_2-C_6)-alkynyl, (C_3-C_9)-cycloalkyl, (C_
5-C_9)-cycloalkenyl, (C_3-C_9)
-cycloalkyl-(C_1-C_4)-alkyl, (
C_5-C_9)-cycloalkenyl-(C_1-C_
4) -alkyl, optionally partially hydrogenated (C
_6~C_1_2)-aryl (which may be substituted as described in claim 2 for R^1), (C
_6~C_1_2)-aryl-(C_1~C_4)-
Alkyl or (C_7-C_1_3)-aroyl-(
C_1 or C_2)-alkyl (both of which may be substituted similarly to the aryls above), 5-7
a monocyclic ring having 8 to 10 ring atoms, each of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms optionally partially hydrogenated heteroaryl, which may be substituted analogously to the aryls mentioned above, or the naturally occurring α-amino acid R^1-CH(NH_2)-COOH Compounds of formula I according to claims 1 and 2 and their physiologically acceptable salt. 4) Formula I according to claims 1 to 3 [wherein R^1 is hydrogen, (C_1 to C_8)-alkyl, (C_
2-C_8)-alkenyl, (C_3-C_9)-cycloalkyl, amino-(C_1-C_4)-alkyl,
(C_2-C_8)-acylamino-(C_1-C_4
)-alkyl, (C_7-C_1_3)-aroylamino-(C_1-C_4)-alkyl, (C_1-C_4
)-alkoxycarbonylamino-(C_1-C_4)
-Alkyl, (C_1-C_4)-alkoxycarbonyl-(C_1-C_1_0)-alkyl, carbamoyl-(C_1-C_1_0)-alkyl, (C_1-C_
4) -Mono- or di-alkylcarbamoyl-(C_
1~C_1_0)-alkyl (alkyl is optionally substituted with phenyl), (C_6~C_1_2)-
Aryl-(C_1~C_6)-alkyl, (C_6~
C_1_2)-aryl-(C_1-C_4)-alkoxycarbonylamino-(C_1-C_4)-alkyl, (C_1-C_4)-alkyl, (C_1-C_4)
-Alkoxy, hydroxyl, halogen, nitro, amino, (C_1-C_4)-alkylamino, di-(C_
1-C_4)-represents (C_6-C_1_2)-aryl which can be mono-, di- or tri-substituted by alkylamino and/or methylenedioxy, R^2 is hydrogen, optionally amino, (C_1-C_6)
-(C_1-C_6)-alkyl, (C_2-C_6) which may be substituted by acylamino or benzoylamino
)-alkenyl, (C_3-C_9)-cycloalkyl, (C_5-C_9)-cycloalkenyl, (C_3-
C_7)-cycloalkyl-(C_1-C_4)-alkyl, (C_6-C_1_2)-aryl or partially hydrogenated aryl, which are respectively (C_1-
C_4)-alkyl, (C_1 or C_2)-alkoxy or halogen), (C_6-
C_1_2)-aryl-(C_1-C_4)-alkyl or (C_7-C_1_3)-aroyl-(C_1
~C_2)-alkyl (both of which may be substituted as defined above in the aryl group), 5-7
a monocyclic ring having 8 to 10 ring atoms, each of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms represents a natural or bicyclic heterocyclic group, or a side chain of a naturally occurring, optionally protected α-amino acid, where R^3 and R^4 together with the atoms that carry them represent an octa-amino acid group; Hydroindole, octahydrocyclopenta[b]pyrrole, spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine], 1,2,3,3a,4,6a-hexahydrocyclopenta [b] Forming a bicyclic or tricyclic heterocyclic ring system selected from the group consisting of pyrrole or indoline] and physiologically acceptable salts thereof. 5) Reacting the fragments in a suitable solvent, if appropriate in the presence of a base and/or a coupling auxiliary, optionally reducing the unsaturated compounds formed as intermediates, such as Schiff bases. the temporarily introduced protecting groups to protect the reactive groups are removed, and the compound thus obtained is subjected to intramolecular cyclization, where appropriate free carboxyl groups are removed. 5. A process for the preparation of compounds of formula I according to claims 1 to 4, which comprises esterifying a compound of formula I with a compound of formula I and, if appropriate, converting the resulting compound into its physiologically acceptable salt. 6) Formulas according to claims 1 to 4 for use as pharmaceuticals
Compound I. 7) Nootropic agent
5. Compounds of formula I according to claims 1 to 4 for use as ). 8) A medicament containing an effective amount of a compound of formula I according to claims 1 to 4 and physiologically acceptable excipients. 9) A process for producing a medicament according to claim 8, which comprises converting the active substance together with excipients and, where appropriate, other additives and/or auxiliaries into a suitable dosage form.